After three decades of false hopes and failures, a pipeline of therapeutic drugs that target the actual root cause of Alzheimer's disease (AD) is now available. Challenging the old paradigm that focused on β‐amyloid peptide (Aβ) aggregation in amyloid plaques, these compounds are designed to prevent the neurotoxicity of Aβ oligomers that form Ca²⁺ permeable pores in the membranes of brain cells. By triggering an intracellular Ca²⁺ overdose, Aβ oligomers induce a cascade of neurotoxic events including oxidative stress, tau hyperphosphorylation, and neuronal loss. Targeting any post‐Ca²⁺ entry steps (e.g., tau) will not address the root cause of the disease. Thus, preventing Aβ oligomers formation and/or blocking their toxicity is by essence the best approach to stop any progression of AD. Three categories of anti‐oligomer compounds are already available: antibodies, synthetic peptides, and small drugs. Independent in silico‐based designs of a peptide (AmyP53) and a monoclonal antibody (PMN310) converged to identify a histidine motif (H13/H14) that is critical for oligomer neutralization. This “histidine trick” can be viewed as the Achilles' heel of Aβ in the fight against AD. Moreover, lipid rafts and especially gangliosides play a critical role in the formation and toxicity of Aβ oligomers. Recognizing AD as a membrane disorder and gangliosides as the key anti‐oligomer targets will provide innovative opportunities to find an efficient cure. A “full efficient” solution would also need to be affordable to anyone, as the number of patients has been following an exponential increase, affecting every part of the globe.

中文翻译：

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阿尔茨海默病治疗的进展：利用 Aβ 寡聚体的致命弱点？

在经历了三年的错误希望和失败之后，现在可以使用一系列针对阿尔茨海默病 (AD) 实际根本原因的治疗药物。挑战专注于淀粉样蛋白斑块中 β-淀粉样肽 (Aβ) 聚集的旧范式，这些化合物旨在防止在脑细胞膜中形成 Ca ²⁺可渗透孔的 Aβ 寡聚体的神经毒性。通过触发细胞内 Ca ²⁺过量，Aβ 寡聚体诱导一系列神经毒性事件，包括氧化应激、tau 过度磷酸化和神经元丢失。靶向任何后Ca ²⁺进入步骤（例如，tau）不会解决疾病的根本原因。因此，防止 Aβ 寡聚体形成和/或阻断其毒性本质上是阻止 AD 任何进展的最佳方法。目前已有三类抗寡聚体化合物：抗体、合成肽和小药。肽 (AmyP53) 和单克隆抗体 (PMN310) 的独立基于计算机的设计融合以识别对寡聚体中和至关重要的组氨酸基序 (H13/H14)。这种“组氨酸把戏”可以看作是Aβ对抗AD的致命弱点。此外，脂筏，尤其是神经节苷脂在 Aβ 寡聚体的形成和毒性中起着关键作用。认识到 AD 是一种膜疾病，神经节苷脂是关键的抗寡聚体靶点，将为找到有效的治疗方法提供创新机会。一个“完全高效”的解决方案也需要任何人都能负担得起，因为患者数量呈指数增长，影响到全球各地。